1. Multimodality therapy for rectal cancer Carlo Aschele Oncologia Medica B Istituto Nazionale per la Ricerca sul Cancro - Genova Carlo Aschele Oncologia Medica B Istituto Nazionale per la Ricerca sul Cancro - Genova Highlights in the management of gastrointestinal cancer Roma - May 21-22, 2010

2. LOCAL FAILURE AND SITE OF RECTAL CANCER tumorodds 95% siteratioc.i. upper0.43 0.24-0.77 third middle/ lower1.0 third p=0.004 Hermanek, 1995

3. EFFECT OF RT ON LOCAL FAILURE AND SITE OF RECTAL CANCER Dutch TME trial cm from 2-y LR, % anal verge RT+TMETMEp 0-55.8 10 0.05 5-101.0 10.1<0.001 10-151.3 3.80.17 NEJM, 2001

4. SOTTO LA RIFLESSIONE PERITONEALE ENTRO 12 CM DALLA RIMA ANALE età-sesso-altezza-peso-condizioni ginecologiche ed ostetriche (nord vs sud europa) anteriore vs posteriore INTERVENTO- RETTOSCOPIA (STR RIGIDO)-RMN CHI?

5. Locally advanced rectal cancer perirectal fat penetration adjacent organ invasion lymphnode infiltration mesorectal fascia (CRM) involvement TRUS - CT scan - MRI

6. Tx neoadiuvante del carcinoma del retto Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach

7. Tx neoadiuvante del carcinoma del retto Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach

10. IMPACT OF POST-OP CMT T3 and/or N+ local failure, % 5-y survival, % GITSG 7175 11 54 Mayo/NCCTG 79-47-5114 53 86-47-519-11 60-70 (4-y) INT 011414 64 NSABP R-02 9 62-65 Compared to surgery alone: ~ 50 ~ 15-25

11. Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004 (NCCTG 794751, 864751; NSABP R01, R02; INT 0114. N=3791) LOCALLY ADVANCED RECTAL CANCER. IMPACT OF ADJUVANT CMT ON SURVIVAL

12. Post-op chemoradiation Compliance46-76 % Acute toxicity26-53 % (grade III-IV) Long-term toxicity46-56 % NCCTG 79-4751 / 86-4751; GITSG 7175 ; NSABP R02; CAO/ARO/AIO 94

13. CAO/ARO/AIO-94 R 50.4 Gy CI FU TME FU x 4 cy TME FU x 4 cy 50.4 Gy CI FU

14. Post-opPre-op p 5-y outcome(n=394)(n=405) Survival % 74 76 0.80 LF % 13 6 0.006 acute toxicity 40 27 0.001 chronic toxicity 24 14 0.01 NEJM 2004 CAO/ARO/AIO-94 TME SURGERY

15. CAO/ARO/AIO-94 declared to sphincter-saving require APR surgery Post 7819 % (15/78) Pre 11639 % (45/116) p 0.004 NEJM 2004 PRE-OP CHEMORADIATION: IMPACT ON SPHINCTER SAVING

16. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT T3-4 and/or N+

17. Pre-op RT vs. surgery alone: Risk of local recurrence in phase III trials

18. Role of chemotherapy PRE-OP RT +/- CONCOMITANT CT pCR, % RTRT + CT EORTC514 FFCD310 Bosset, NEJM 2006; Gerard, JCO 2006

19. Role of chemotherapy PRE-OP RT +/- CONCOMITANT CT 5-y LR, % RTRT + CT EORTC178 FFCD168 Bosset, NEJM 2006; Gerard, JCO 2006

20. NSABP R-04 RT + Capecitabine +/- oxaliplatin S RT + CI 5-FU +/- oxaliplatin R N=1460

21. R RT 50.4 Gy FU 225 mg/m 2 /day PVI OXA 60 mg/m 2 weekly x 6 RT 50.4 Gy FU 225 mg/m 2 /day PVI TMETME 6-8 wks n=747 n=598 STAR-01 ACCORD ypT0(N0) 16% p=0.94 R RT 50 Gy CAPE 1600 mg/m 2 /day OXA 50 mg/m 2 weekly x 5 RT 45 Gy CAPE 1600 mg/m 2 /day TMETME 6-8 wks 14% 19% p=0.11 ASCO ‘09

22. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT T3-4 and/or N+

23. 5–10% Blunt dissection TME LR 20–40%

24. Fascial plane In mesorectumIn/on muscularis Dataset for colorectal cancer (2° edition), RCOP, 2007

25. SURGERY QUALITY: EFFECT OF THE PLANE OF SURGERY ON LOCAL RECURRENCE

26. Circumferential resection margin

27. Nagtegaal, I. D. et al. J Clin Oncol; 26:303-312 2008 LOCAL RECURRENCE AND CRM

28. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT T3-4 and/or N+

29. FU-based adjuvant chemotherapy in rectal cancer patients. QUASAR study (n=948). survival

30. n = 3239 Effect of FU-based adjuvant chemotherapy in colon and rectal cancer patients. QUASAR study Recurrence

31. Effect of adjuvant FU-based chemotherapy in rectal cancer patients included in the QUASAR study Recurrence at any time n = 948 Lancet 2008; 371: 1503

32. CAO/ARO/AIO-94 R 50.4 Gy CI FU TME FU x 4 cy TME FU x 4 cy 50.4 Gy CI FU

33. Gunderson, L. L. et al. J Clin Oncol; 22:1785-1796 2004 (NCCTG 794751, 864751; NSABP R01, R02; INT 0114. N=3791) LOCALLY ADVANCED RECTAL CANCER. IMPACT OF ADJUVANT CMT ON SURVIVAL Surg +/- RT + Adj Chemo

35. ECOG 5204 * RT + bolus or CI FU ± LV, or Cape or NSABPR 04

36. JCO, 2007 Effect of adjuvant chemotherapy in pts with good and poor response to pre-op treatment DFS

37. Tx neoadiuvante del carcinoma del retto Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach Patient selection - tumor location - tumor stage Standard treatment Chemotherapy –role (concomitant and adjuvant) –simplification / potentiation Surgery / pathology Standard vs selective approach

38. Standard treatment of locally advanced rectal cancer TMETME 45-50.4 Gy CT RT Optimal for every LARC patient?

39. n=188 (TRUS 130 / MRI 58) 22 % node + after pre-op CRT

40. n3-y LR5-y LR routine pre 6744%5% selective post 67611%12 % HR=0.39 (95% CI 0.27-0.58); p<0.0001

41. MERKEL et al 2001 pT3<5mm, N any T2 and early T3 tumours <5mm have 85-90% 5 year cancer specific survival.

42. STANDARD vs SELECTIVE APPROACH almeno 7-8 cm dalla rima anale infiltrazione grasso < 5 mm (MERCURY) non evidenza di linfonodi patologici margine radiale atteso di almeno 2 mm chirurgo dedicato TME con mesoretto integro e CRM - pT3a-bN0 (almeno 12 linfonodi negativi) G1-G2 patients’ preference

43. Rectal cancer: adjuvant / neoadjuvant treatment SURGEON MEDICAL ONCOLOGIST RADIOTHERAPIST CURE QOL PATHOLOGIST STOMA THERAPIST NURSE RADIOLOGIST